This invention relates to antiparasitic agents and in particular to compounds related to the avermectins and milbemycins, but having a novel substituent group at the 25-position and to a process for their preparation.
The avermectins are a group of broad spectrum antiparasitic agents referred to previously as the C-076 compounds. They are produced by fermenting a strain of the microorganism Streptomyces avermitilis ATCC 31267, 31271 or 31272 under aerobic conditions in an aqueous nutrient medium containing inorganic salts and assimilable sources of carbon and nitrogen. The morphological and cultural properties of the strains ATCC 31267, 31271 and 31272 are described in detail in British Patent Specification no. 1573955 which also describes the isolation and the chemical structure of the eight individual components which make up the C-076 complex.
The milbemycins are structurally related macrolide antibiotics lacking the sugar residues at the 13-position. They may be produced by fermentation, for example, as described in British Patent Specification 1390336 and European Patent Application 170006.
The aglycones are derivable from the avermectins by hydrolysis to remove the sugar residues to produce a similar compound having a hydroxy group at the 13-position.
In our European Patent Application publication no. 0214731 we disclose that by adding certain specified carboxylic acids, or derivatives thereof, to the fermentation of an avermectin producing organism it is possible to obtain novel compounds, related to the avermectins but having an unnatural substituent group at the 25-position in place of the isopropyl or sec-butyl group which is normally present.
The novel compounds produced are characterised in that the substituent group at the 25-position is alpha-branched i.e. the carbon atom attached to the C-25 ring position is a secondary carbon atom linked to two further carbon atoms.
In our co-pending European patent application nos. 88.300354.3 and 88300426.9 we describe and claim new mutant strains of the microorganism Streptomyces avermitilis lacking branched-chain 2-oxo acid dehydrogenase activity. Said strains have been deposited in the American Type Culture Collection, Rockville, Md. under the designations Streptomyces avermitilis ATCC 53567, ATCC 53568 and ATCC 53692. In our British patent application 87.26730 we disclose that, by using these new mutant strains of Streptomyces avermitilis it is possible to obtain a further range of novel avermectin derivatives, not previously obtainable, wherein the C-25 substituent is linked by an unbranched (primary) carbon atom. These avermectins are prepared by fermenting the afore-mentioned microorganisms in the presence of the appropriate carboxylic acid or a salt, ester or amide thereof or oxidative precursor therefor. It has now been discovered that certain carboxylic acids, which do not incorporate when added to the fermentation as the free carboxylic acid or a simple ester or thioester, will produce novel avermectins if added in the form of an N-alkanoyl cysteamine thioester.
N-alkanoyl cysteamine thioesters have been used in biosynthetic studies for other purposes, see R. C. Hutchinson et. al., J. Amer. Chem. Soc., 1987, 109, 1253-1255 or D. E. Cane et. al. J. Amer. Chem. Soc., 1987, 109, 1255-1257 or J. A. Robinson et. al., J. Chem. Soc., Chem. Comm. 1988, 4.